New Caspase-1 inhibitor by scaffold hopping into bio-inspired 3D-fragment space

Bioorg Med Chem Lett. 2017 Dec 15;27(24):5373-5377. doi: 10.1016/j.bmcl.2017.11.015. Epub 2017 Nov 9.

Abstract

Virtual fragmentation of a library of 12,000 compounds inspired by natural products led to a dataset of 153,000 fragments that was used as a source to identify effective P2-P3 scaffold replacement solutions for peptidic Caspase-1 inhibitors. Our strategy led to the identification of an original 2-azabicyclo-octane scaffold (2-ABO) that was further elaborated into the potent Caspase-1 inhibitor CD10847 (IC50 = 17 nM). The crystal structure of Caspase-1 in complex with CD10847 was obtained, and its binding mode was shown to be similar to the one predicted by docking and in good agreement with other known inhibitors.

Keywords: 3D fragments; Caspase-1; Docking; Natural product; Scaffold hopping.

MeSH terms

  • 4-Butyrolactone / analogs & derivatives*
  • 4-Butyrolactone / chemical synthesis
  • 4-Butyrolactone / chemistry
  • 4-Butyrolactone / metabolism
  • Azabicyclo Compounds / chemistry
  • Azabicyclo Compounds / metabolism
  • Binding Sites
  • Biological Products / chemistry
  • Biological Products / metabolism
  • Caspase 1 / chemistry*
  • Caspase 1 / metabolism
  • Caspase Inhibitors / chemistry*
  • Caspase Inhibitors / metabolism
  • Crystallography, X-Ray
  • Dipeptides / chemical synthesis
  • Dipeptides / chemistry*
  • Dipeptides / metabolism
  • Hydrogen Bonding
  • Inhibitory Concentration 50
  • Molecular Conformation
  • Molecular Docking Simulation
  • Protein Structure, Tertiary

Substances

  • Azabicyclo Compounds
  • Biological Products
  • CD10847
  • Caspase Inhibitors
  • Dipeptides
  • Caspase 1
  • 4-Butyrolactone